NMN v. NR - Which Is A Better NAD Precursor?

This article has been updated. For the latest version, head over to

Science of NAD:

https://www.scienceofnad.com/post/nmn-v-nr

 

NMN versus NR

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You may have heard of the exciting experiments in which mice age backwards when their NAD is replenished -- and it might work for humans too! -- but which of the four major NAD precursors should you be taking if you want to try it out?

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This chart compares NA, NAM, NR, and NMN.  

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But if you want to cut to the chase, the final two to consider are Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN).

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NR is easy to buy on amazon, but for multi-bottle and subscription pricing you will do better by purchasing directly from ChromaDex, which is the only licensed manufacturer. ChromaDex sells it as "Tru Niagen."

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NMN is also available on amazon from a number of distributors, although it's not as clear who manufactures it, and it tends to be more expensive than NR.

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What's the Difference Between NR and NMN?

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NR and NMN are chemically very similar. If you add a phosphate to NR, you get NMN.

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The primary advantages of NR as compared to the other NAD precursors are:

 

(1) NR works in all types of cells

(2) NR's effectiveness does not diminish when you age or experience stress

(3) NR has been tested for safety and efficacy in humans

(4) There are a LOT of studies underway examining NR

(5) Niagen is stable at room temperature

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For example, here is a brand new (Feb 2019) double-blind, cross-over, placebo-controlled human study showing that NR improves physical performance in older adults. Those kinds of studies may emerge eventually for NMN, but we don't have them yet.

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Also, NMN can't pass through most or all cell walls, and therefore cannot directly replenish cellular NAD. (This article speculates that NMN might be able to enter some types of cells, although perhaps not in great quantity, but this rebuttal disputes the evidence that NMN can enter the cells. Dr. Brenner says there is "no credible evidence" that NMN can enter cells. And Dr. Sinclair concedes that NMN degrades at room temperature.)

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Nonetheless, NMN shows many of the same effects as NR, but for a tricky reason: Our bodies are capable of stripping off the phosphate and turning the NMN into NR. So when you take NMN, you end up with NR anyway, and your cells can benefit in the same way.

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This study from April 2020 found that NR entered brain cells of mice and had a therapeutic effect, but NMN could not enter the cells and had no effect.

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And this mouse study from May 2020 seems to prove that NMN gets converted to NR before it enters the cells, because when they stopped the NMN from converting to NR, the NMN had no effect at all.

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Not only is there less research on NMN -- including less human research -- NMN also is more difficult to synthesize, and so it tends to be more expensive. You might for example see a bottle of NMN that looks like it costs the same as a bottle of NR, but it is made up of additional filler ingredients, like tumeric root, or only contains half as many pills.

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And really an NMN capsule -- even if kept refrigerated since manufacture -- will give you about about 30% LESS NAD than the same weight capsule of NR, because about 30% of the weight of NMN consists of phosphates that are just going to get stripped off anyway.[1]

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Although NMN should function similarly to NR, and many experiments suggest that it does, there might also be some differences.

 

This study, for example, released on September 26, 2018, suggests that NMN accumulation is actually toxic to damaged nerves, whereas NR delayed nerve degeneration. But on the other hand, it is possible that future experiments will show that NMN outperforms NR in replenishing NAD in some circumstances, although I have not seen any such experiment yet. [UPDATE 1/2019:] And this study published on November 15, 2018 suggests that NR may be five times more effective than NMN at driving up intracellular NAD in skeletal muscles. [UPDATE 12/2019:] And there is new evidence now that NMN gets converted to NR before entering the cell. UPDATE 01/2020: and MORE evidence that NMN gets converted to NR before entering the cell.

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Chris Masterjohn, Phd, on the Peter Attia podcast, agrees that oral NMN is a waste, and at best just gets turned into NR:

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"I would bet money that oral NMN is not absorbed intact, and that’s because NMN has a charged phosphate group on it, and generally charged phosphates cannot cross cells, and so they are hydrolyzed. And even if it were true that there were transporters in the intestine that could take up NMN intact, it probably still would not be absorbed intact because the phosphatases in the small intestine cleave the phosphates off of everything that you are eat non-specifically, because generally phosphates can’t cross cells. So I doubt that the NMN gets in there intact, and if anything maybe it gets cleaved to NR, and the NR does. I believe the NR gets there intact because that’s what the Rabinowitz group’s paper showed."

 

[UPDATE 12/2019:] There has been a great deal of controversy over suggestions that NR gets ground to NAM in the or liver, which has caused some people to suggest that NR is just expensive NAM, and a number people have told me they stopped taking NR because of its lack of bioavailability.

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Although the full story remains untold there are good reasons not to draw too-broad conclusions from single experiments that do not find NR where they are looking for it. 

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Dr. Charles Brenner, the world's leading authority on NR -- the scientist who discovered NR's role as a vitamin, and whose lab has been studying NR for at least the past 15 years --  outlined on Twitter the difficultly of measuring NR in humans and the evidence that oral NR is effective as NR:

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Let's start with how NR elevates NAD in different tissues in mice. 

 

Our approach uses quantitative targeted metabolomics. This means we measure concentrations of NAD+, NADP+, ADPR, NAAD, NMN, NAMN, NR, NAM, NA plus several methylated/oxidized forms of NAM & other compounds simultaneously. Ppl that use cycling assays cannot get quantitative data.

Ppl that use metabolomic methods without internal standards do not get quantitative data. Ppl that don't know how to properly extract samples or that sacrifice animals at different times of day do not get valid data.

 

Our data showed that oral NR has a different time course than NAM or NA in elevating liver NAD metabolome & produces more NAD than the other B3s per equivalent dose. See this figure plus others in the same Nature article.

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NR clearly acts as NR in elevating liver NAD. In 15', if you have put NA, NAM or NR in a mouse's stomach, you see that form of B3 in the liver. In liver, NR and NAM behave differently. NR produces much more ADPR than NAM, suggesting that high dose NAM depresses SIRT activity.

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In other tissues, there is a complication that you cannot see circulating NR in blood because of an extraction issue. However, you can see NR elevate cardiac NAD in failing mouse hearts that spike up expression of the NRK2 gene and depress NAMPT. NAM can't do that.

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Other genetic & pharmacological experiments show that NR acts as NR in heart, skeletal muscle, nerve & brain. Both NAD & NMN work as NR in multiple target tissues. There is no credible evidence for transport of NAD or NMN into any cell no matter whether injected or taken orally.

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There are additional experiments that address bioavailability in mice, rats & humans that we are doing. It's irresponsible to make claims that have not been vetted by peer reviewers so we'll leave it there for now.

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And in this study, NR dietary supplementation protected against alcohol-induced depression-like behaviors in mice, possibly by altering the composition of the gut microbiota. Acting directly on the gut microbiome to deliver benefits would not require bioavailability to cell tissues elsewhere in the body at all.

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CONCLUSION

Right now, Nicotinamide Riboside appears to be the most effective, most efficient, and most studied way to replenish NAD. In most circumstances, NMN is likely to perform similarly to NR, but I have not seen any studies that suggest NMN performs better than NR.

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If NMN were stable at room temperature, available from a safety-tested source, and cost significantly less than NR, it would certainly be worth considering. Right now, however, for NMN the price is higher, the sourcing is unclear, an equal weight of NMN contains 30% less of the NR component, and the research on NMN is behind. Until that changes, NR seems like the obvious choice.

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But should you be replenishing your NAD at all?

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1. Why I Tell All My Friends to Take NR

2. Basis v. Niagen Comparison Chart

3. Other NAD Precursors

4. One Simple Reason to Avoid Elysium Basis

5. How & Why to Make Your Own Basis

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[1] Molecular weight of NMN is 334 grams/mole; Molecular weight of NR is 255 grams/mole.